Thymidylate synthase (TS) is a target for antifolate-based chemotherapies of microbial and human diseases. Here, ligand-based, synthetic, and X-ray crystallography studies led to the discovery of 6-(3-cyanobenzoyloxy)-2-oxo-2H-naphto[1,8-bc]furan, a novel inhibitor with a Ki of 310 nM against Pneumocystis carinii TS. The X-ray ternary complex with Escherichia coli TS revealed, for the first time, displacement of the substrate toward the dimeric protein interface, thus providing new opportunities for further design of specific inhibitors of microbial pathogens.

Ferrari, S., Calò, S., Leone, R., Luciani, R., Costantino, L., Sammak, S., et al. (2013). 2'-Deoxyuridine 5'-monophosphate substrate displacement in thymidylate synthase through 6-hydroxy-2H-naphtho[1,8-bc]furan-2-one derivatives. JOURNAL OF MEDICINAL CHEMISTRY, 56(22), 9356-9360 [10.1021/jm4014086].

2'-Deoxyuridine 5'-monophosphate substrate displacement in thymidylate synthase through 6-hydroxy-2H-naphtho[1,8-bc]furan-2-one derivatives

LEONE, ROSALIDA;DI PISA, FLAVIO;POZZI, CECILIA;MANGANI, STEFANO;
2013-01-01

Abstract

Thymidylate synthase (TS) is a target for antifolate-based chemotherapies of microbial and human diseases. Here, ligand-based, synthetic, and X-ray crystallography studies led to the discovery of 6-(3-cyanobenzoyloxy)-2-oxo-2H-naphto[1,8-bc]furan, a novel inhibitor with a Ki of 310 nM against Pneumocystis carinii TS. The X-ray ternary complex with Escherichia coli TS revealed, for the first time, displacement of the substrate toward the dimeric protein interface, thus providing new opportunities for further design of specific inhibitors of microbial pathogens.
Ferrari, S., Calò, S., Leone, R., Luciani, R., Costantino, L., Sammak, S., et al. (2013). 2'-Deoxyuridine 5'-monophosphate substrate displacement in thymidylate synthase through 6-hydroxy-2H-naphtho[1,8-bc]furan-2-one derivatives. JOURNAL OF MEDICINAL CHEMISTRY, 56(22), 9356-9360 [10.1021/jm4014086].
File in questo prodotto:
File Dimensione Formato  
2013 JMedChem TS.pdf

non disponibili

Tipologia: PDF editoriale
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 754.62 kB
Formato Adobe PDF
754.62 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/974776